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Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Neuroblastoma

Information source: Children's Oncology Group
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Neuroblastoma

Intervention: filgrastim (Biological); sargramostim (Biological); carboplatin (Drug); cisplatin (Drug); cyclophosphamide (Drug); doxorubicin hydrochloride (Drug); etoposide (Drug); etoposide phosphate (Drug); ifosfamide (Drug); isotretinoin (Drug); melphalan (Drug); thiotepa (Drug); vincristine sulfate (Drug); conventional surgery (Procedure); peripheral blood stem cell transplantation (Procedure); radiation therapy (Radiation)

Phase: Phase 2

Status: Completed

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Stephan A. Grupp, MD, PhD, Study Chair, Affiliation: Children's Hospital of Philadelphia

Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy followed by peripheral stem cell transplantation in treating children who have newly diagnosed neuroblastoma.

Clinical Details

Official title: A Pilot Study Of Tandem High Dose Chemotherapy With Stem Cell Rescue Following Induction Therapy In Children With High Risk Neuroblastoma

Study design: Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Transplant-related mortality

Secondary outcome:

Incidence of symptomatic CMV, disseminated adenovirus infection, or EBV-LPD

Event-free Survival

Detailed description: OBJECTIVES:

- Determine the toxicity and feasibility of high-dose thiotepa and cyclophosphamide with

autologous peripheral blood stem cell (PBSC) transplantation and sargramostim (GM-CSF) followed by high-dose carboplatin, etoposide, and melphalan with second PBSC transplantation, GM-CSF, and isotretinoin after induction in children with newly diagnosed high-risk neuroblastoma.

- Determine the role of the meta-iodobenzylguanidine (MIBG) scan in assessing response to

tandem transplantation and minimal residual disease therapy in these patients.

- Determine the feasibility of quantitative polymerase chain reaction for

neuroblastoma-specific ribonucleic acids at specific stages of treatment as a prognostic indicator of outcome in these patients.

- Determine the immune recovery by quantitation of lymphocyte subsets in these patients

and limited functional analysis after completion of this regimen. OUTLINE: This is a multicenter study. Patients are stratified according to peripheral blood stem cell (PBSC) selection (selected PBSCs vs unselected PBSCs). (Selected PBSC stratum closed to accrual as of 7/17/02.)

- Induction/harvest:

- Course 1: Patients receive etoposide (VP-16) IV over 1 hour on days 2-4, cisplatin

IV over 6 hours (beginning after VP-16 infusion) on days 1-5, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.

- Course 2: Patients receive vincristine IV and doxorubicin IV over 15 minutes on

day 1, cyclophosphamide IV over 6 hours on days 1 and 2, and sargramostim (GM-CSF) SC beginning on day 3 and continuing until PBSC are harvested. Beginning after completion of course 2 and when blood counts recover, autologous PBSC are harvested.

- Course 3: Patients receive VP-16 IV over 1 hour and ifosfamide IV over 1 hour on

days 1-5 and G-CSF SC beginning on day 6 and continuing until blood counts recover.

- Course 4: Patients receive VP-16 IV over 1 hour on days 1-3, carboplatin IV over 2

hours (beginning after VP-16 infusion) on days 1 and 2, and G-CSF SC beginning on day 4 and continuing until blood counts recover.

- Course 5: Patients receive treatment as in course 2 but supported by G-CSF.

Courses 1-5 each last 3-4 weeks. Patients undergo resection of the primary tumor after course 4 or 5 unless primary resection was completed at diagnosis (which is not recommended), no primary site is found, or the primary site is unresectable. Patients complete courses 1-5 and then proceed to the first conditioning/PBSC transplantation (PBSCT) in the absence of disease progression or unacceptable toxicity.

- First conditioning/PBSCT: Patients receive high-dose thiotepa IV on days -7 to -5 and

cyclophosphamide IV over 1 hour on days - 5 to -2. CD34+ PBSC are reinfused on day 0.

GM-CSF is administered SC beginning on day 5 and continuing until blood counts recover. If blood counts have not recovered by day 28, unselected PBSC are reinfused. In the absence of disease progression or unacceptable toxicity, patients proceed to the second conditioning/PBSCT.

- Second conditioning/PBSCT: Beginning within 6-8 weeks after initiating the first

conditioning, patients receive high-dose carboplatin IV continuously and etoposide

phosphate IV continuously on days - 7 to -4 and melphalan IV on days -7 to -5. PBSC and

GM-CSF are administered as in the first PBSCT. Beginning no earlier than day 28 after the second PBSCT, patients undergo local radiotherapy to the primary site and sites that are positive by meta-iodobenzylguanidine scan after induction twice a day for 7 days (or once a day for 12 days if twice daily dosing is not possible). Beginning on day 90 after the second PBSCT, patients receive oral isotretinoin twice a day for 2 weeks. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 31-39 patients will be accrued for this study within 22 months.

Eligibility

Minimum age: N/A. Maximum age: 30 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Newly diagnosed high-risk neuroblastoma

- Histologically proven AND/OR

- Bone marrow specimen showing clumps of tumor cells accompanied by elevated

urinary catecholamines

- Age 1-30:

- Must meet one of the following INSS staging criteria:

- Stage IV regardless of biologic factors

- Stage IIa/IIb with MYCN oncogene amplification (greater than 10) and

unfavorable pathology

- Stage III with MYCN oncogene amplification (greater than 10) or

unfavorable pathology

- Initially stage I, II, or IVS, that has progressed without interval

chemotherapy

- Under age 1:

- INSS stage III, IV, or IVS with MYCN amplification (greater than 10)

- Must enter neuroblastoma biology study COG-ANBL00B1 within 2 weeks of diagnosis and

before entry on this study PATIENT CHARACTERISTICS: Age:

- 30 and under at original diagnosis

Performance status:

- Not specified

Life expectancy:

- Not specified

Hematopoietic:

- Not specified

Hepatic:

- Not specified

Renal:

- Not specified

Other:

- Not pregnant or nursing

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy:

- Not specified

Chemotherapy:

- See Disease Characteristics

- No more than 1 prior course of chemotherapy on the intergroup low- or

intermediate-risk neuroblastoma studies prior to determination of MYCN status and Shimada histology Endocrine therapy:

- Not specified

Radiotherapy:

- Prior emergent radiotherapy to sites of function- or life-threatening neuroblastoma

allowed Surgery:

- Not specified

Other:

- No other prior systemic therapy for neuroblastoma

Locations and Contacts

AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish RiteCampus, Atlanta, Georgia 30342, United States

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States

Floating Hospital for Children, Boston, Massachusetts 02111, United States

CCOP - Columbia River Oncology Program, Portland, Oregon 97225, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Baylor College of Medicine, Houston, Texas 77030, United States

CCOP - Scott and White Hospital, Temple, Texas 76508, United States

Princess Margaret Hospital for Children, Perth, Western Australia 6001, Australia

CCOP - Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, United States

Additional Information

Clinical trial summary from the National Cancer Institute's PDQ® database

Related publications:

Marcus KJ, Shamberger R, Litman H, von Allmen D, Grupp SA, Nancarrow CM, Goldwein J, Grier HE, Diller L. Primary tumor control in patients with stage 3/4 unfavorable neuroblastoma treated with tandem double autologous stem cell transplants. J Pediatr Hematol Oncol. 2003 Dec;25(12):934-40.

Kletzel M, Katzenstein HM, Haut PR, Yu AL, Morgan E, Reynolds M, Geissler G, Marymount MH, Liu D, Kalapurakal JA, Shore RM, Bardo DM, Schmoldt J, Rademaker AW, Cohn SL. Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol. 2002 May 1;20(9):2284-92.

Donovan J, Temel J, Zuckerman A, Gribben J, Fang J, Pierson G, Ross A, Diller L, Grupp SA. CD34 selection as a stem cell purging strategy for neuroblastoma: preclinical and clinical studies. Med Pediatr Oncol. 2000 Dec;35(6):677-82.

Grupp SA, Stern JW, Bunin N, Nancarrow C, Adams R, Gorlin JB, Griffin G, Diller L. Rapid-sequence tandem transplant for children with high-risk neuroblastoma. Med Pediatr Oncol. 2000 Dec;35(6):696-700.

Grupp SA, Stern JW, Bunin N, Nancarrow C, Ross AA, Mogul M, Adams R, Grier HE, Gorlin JB, Shamberger R, Marcus K, Neuberg D, Weinstein HJ, Diller L. Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol. 2000 Jul;18(13):2567-75.

Starting date: April 2001
Last updated: February 12, 2014

Page last updated: August 23, 2015

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